Use of compounds

ABSTRACT

The invention relates to the use of a hypolipidemic agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or delay of the progression to overt diabetes, especially type 2, prevention or reduction of microvascular complications (eg, retinopathy, neurophathy, nephropathy), prevention or reduction of excessive cardiovascular morbidity (eg, myocardial infarction, arterial occlusive disease, atherosclerosis and stroke) and cardiovascular mortality, prevention of cancer and reduction of cancer deaths. Additionally, the invention relates to the use of a treatment for diseases and conditions that are associated with IGM, IGT or IFG.

Impaired Glucose Metabolism (IGM) is defined by blood glucose levelsthat are above the normal range but are not high enough to meet thediagnostic criteria for type 2 diabetes mellitus. The incidence of IGMvaries from country to country, but usually occurs 2-3 times morefrequently than overt diabetes. Until recently, individuals with IGMwere felt to be pre-diabetics, but data from several epidemiologicstudies argue that subjects with IGM are heterogeneous with respect totheir risk of diabetes and their risk of cardiovascular morbidity andmortality. The data suggest that subjects with IGM, in particular IGT,do not always develop diabetes, but whether they are diabetic or not,they are, nonetheless, at high risk for cardiovascular morbidity andmortality.

Among subjects with IGM, about 58% have Impaired Glucose Tolerance(IGT), another 29% have Impaired Fasting Glucose (IFG), and 13% haveboth abnormalities (IFG/IGT). IGT is characterized by elevatedpostprandial (post-meal) hyperglycemia while IFG has been defined by theADA (see Table below) on the basis of fasting glycemic values.

The categories of Normal Glucose Tolerance (NGT), IGM and type 2diabetes mellitus were defined by the ADA in 1997 as follows: Type 2Diabetes NGT IGM mellitus IFG FPG level <6.1 mmol/L 6.1-7 mmol/L >7mmol/L (<110 mg/dl) (110-126 mg/dl)  >126 mg/dl) And and/or or IGT 2 hpostprandial <7.8 mmol/l  7.8-11.1 mmol/L   >11.1 mmol/L   glucose level(<140 mg/dl) (140-220 mg/dl) (>200 mg/dl) (75 g OGTT *⁾)*⁾ These criteria were defined using the WHO recommended conditions foradministration of an oral glucose tolerance test (OGTT), i.e., the oraladministration of a glucose load containing the equivalent of 75 g ofanhydrous glucose dissolved in water with a blood sample taken 2 hourslater to analyze the post-prandial glucose. Other OGTT test conditionshave confirmed the associated risks of the IGT and IFG categoriesincluding: 1) using 50 g glucose instead of 75 g,# 2) using a casual (non-fasting) glucose sample as the analyte, and 3)analyzing the post-prandial glucose at 1 hour rather than 2 hourspost-glucose load. Under all of these conditions, the glycemiccategories defined above have been linked to the increased risksdescribed below, but the standardized OGTT is preferred in order tominimize variations in test results.

Individuals with IGM, especially those with the subcategory IFG, areknown to have a significantly higher rate of progression to diabetesthan normoglycemic individuals and are known to be high atcardiovascular risk, especiallly if they develop diabetes.Interestingly, subjects with IGM, more specifically those with thesubcategory IGT, have a high incidence of cancer, cardiovasculardiseases and mortality even if they never develop diabetes. Therefore,IGM and more specifically, the subgroup IFG, appears to be at highcardiovascular risk, especially after patients become overtly diabetic.IGT, on the other hand, is associated with a high risk for cancer,cardiovascular disease and mortality in nondiabetics and diabetics. Theincreased risk associated with IGT is independent of all other knowncardiovascular risk factors including age, sex, hypertension, low HDLand high LDL cholesterol levels [Lancet 1999; 354: 617-621].

One mechanism through which IGM, and more specifically, IGT, has beenlinked to micro- and macroangiopathic complications in the absence ofthe abnormal FPG characteristic of diabetics, is postprandialhyperglycemia. Isolated postprandial hyperglycemia, even innondiabetics, has been shown to reduce the natural free-radical trappingagents (TRAP) that are present in serum. Decreasing the level of TRAPhas been shown, under experimental conditions, to be associated with anincrease in free radical formation and increased oxidative stress. Thesefree radicals have been implicated in the pathological microvascular andmacrovascular changes associated with atherosclerosis, cardiovascularmorbidity and mortality, and cancer [Ceriello, A, Diabetic Medicine 15:188-193, 1998]. The decrease of natural antioxidants like TRAP duringpostprandial hyperglycemia may explain the increased cardiovascular riskin subjects with IGM, and specifically IGT, that do not developdiabetes. The fact that IGT is an independent risk factor innon-diabetics as well as diabetics justifies it as a new indication,separate from diabetes, for prevention and treatment of cardiovascularmorbidity and mortality as well as cancer. IGM is associated withfollowing potential diseases or conditions: 1.) progression to overtdiabetes mellitus type 2 (Code 250.2 of the International Classificationof Diseases 9^(th) version =ICD-9 Code 250.2) [Diabetes Research andClinical Practice 1998; 40: S1-S2]; 2.) increased microvascularcomplications of diabetes especially retinopathy and other ophthalmiccomplications of diabetes (ICD-9 code 250.5), nephropathy (ICD-9 code250.4), neuropathy (ICD-9 code 250.6) [Diabetes Care 2000; 23:1113-1118], and peripheral angiopathy or gangrene (ICD-9 code 250.7);3.) increased cardiovascular morbidity (ICD-9 codes 410-414) especiallymyocardial infarctions (ICD-9 code 410), coronary heart disease oratherosclerosis (ICD-9 code 414) and other acute and subacute forms ofcoronary ischemia (ICD-9 code 411); 4.) excess cerebrovascular diseaseslike stroke (ICD-9 codes 430-438) [Circulation 1998; 98: 2513-2519]);5.) increased cardiovascular mortality (ICD-9 codes 390-459) [Lancet1999; 354: 617-621], and sudden death (ICD-9 code 798.1); 6.) higherincidences and mortality rates of malignant neoplasms (ICD-9 codes140-208) [Am J Epidemiol. 1990; 131: 254-262, Diabetologia 1999; 42:1050-1054]. Other metabolic disturbances that are associated with IGMinclude dyslipidemia (ICD-9 code 272), hyperuricemia (ICD-9 code 790.6)as well as hypertension (ICD-9 codes 401-404) and angina pectoris (ICD-9code 413.9) [Ann Int Med 1998; 128: 524-533].

Clearly, the broad spectrum of diseases and conditions that are linkedto IGM, and especially IGT, represents an area of tremendous medicalneed. Many of the same diseases and conditions have been associated withboth IGM and diabetes, but only recently has it been possible toidentify that that the nondiabetic population that has IGM, andespecially IGT, should be an indication for prevention and treatment.Accordingly, in subjects with IGM and especially IGT and/or IFG, therestoration of early phase insulin secretion and/or the reduction ofprandial hyperglycemia should help to prevent or delay the progressionto overt diabetes and to prevent or reduce microvascular complicationsassociated with diabetes by preventing the development of the overtdiabetes. In addition, in individuals with IGM and especially those withIGT and/or IFG, the restoration of early phase insulin secretion and/orreduction of postprandial hyperglycemia should also prevent or reducethe excessive cardiovascular morbidity and mortality, and prevent canceror reduce its mortality in individuals.

Thus the stage between normoglycemia and type 2 diabetes mellitus,especially the glycemic stage, is becoming of major interest and thereis a strong need for a method to inhibit or delay the progression totype 2 diabetes mellitus, and also the variety of cardiovascular andmicrovascular conditions and diseases as well as cancer that have beenassociated with IGM and especially IFG and/or IGT.

It has unexpectedly been found that hypoglycemic agents such as insulinsecretion enhancers can be used to prevent or delay the progression toovert diabetes, to reduce microvascular complications of diabetes, toreduce vascular, especially cardiovascular, mortality and morbidity,especially cardiovascular morbidity and mortality, and to reduceincreased mortality related to cancer in individuals with IGT and/orIFG.

Hypoglycemic agents comprise, for example, an insulin secretion enhanceror an insulin sensitivity enhancer (insulin resistance deblocker) orinsulin of, if appropriate, in each case a pharmaceutically acceptablesalt thereof.

Insulin secretion enhancers are active ingredients that have theproperty to promote the secretion of insulin from pancreatic β-cells.

An insulin secretion enhancer (also called insulin secretogogue andinsulinotropic agent) is, for example, a shortacting or a long-actinghypoglycemic agent.

A short-acting hypoglycemic is, for example, a phenylacetic acidderivative, furthermore gliquidone.

A corresponding phenylalanine derivative is, for example, nateglinide[N-(trans-4- isopropylcyclohexylcarbonyl)-D-phenylalanine] (cf. EP196222 and EP 526171) of the formula

and repaglinide[(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl}benzoicacid]; and in free form or, if appropriate, in each case apharmaceutically acceptable salt thereof.

The term nateglinide likewise comprises crystal modifications such asdisclosed in EP 0526171 B1 or U.S. Pat. No. 5,488,510, respectively, thesubject matter of which, especially with respect to the identification,manufacture and characterization of crystal modifications, is herewithincorporated by reference to this application, especially the subjectmatter of claims 8 to 10 of said U.S. patent (referring to H-formcrystal modification) as well as the corresponding references to theB-type crystal modification in EP 196222 B1 the subject matter of which,especially with respect to the identification, manufacture andcharacterization of the B-form crystal modification. Preferably, in thepresent invention, the B- or H-type, more preferably the H-type, isused.

A longacting hypoglycemic is, for example, a biguanide derivative or asulphonyl urea derivative.

An approriate biguanide is, for example, metformin or, if appropriate, apharmaceutically acceptable salt thereof, especially the hydrochloridethereof.

Examples of sulfonylurea derivatives (SU) are, especially those whichpromote the secretion of insulin from pancreatic β-cells by transmittingsignals of insulin secretion via SU receptors in the cell membrane,including (but are not limited to) tolbutamide; chlorpropamide;tolazamide; acetohexamide;4-chloro-N-[(1-pyrolidinylamino)carbonyl]-benzensulfonamide(glycopyramide); glibenclamide (glyburide); gliclazide;1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;glymidine; glypinamide; phenbutamide; and tolylcyclamide, or, ifappropriate, in each case a pharmaceutically acceptable salt thereof.

Insulin secretion enhancers furthermore include the representatives ofthe new generation of SUs such as calcium(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionatedihydrate (KAD-1229) and glimepiride (Hoe 490); and in free orpharmaceutically acceptable salt form.

Insulin secretion enhancers likewise include DPP-IV inhibitors, GLP1 andGLP1 agonists.

DPP-IV is a serine protease and catalyses cleavage of N-terminal Xaa-Proor XaaAla dipeptide residues omcluding glucagon-like protein-1 (GLP-1).Corresponding inhibitors of DPP-IV increase circulating concentrationsof GLP-1 and therefore increasing insulin secretion.

Representatives of DPP-IV inhibitors are described in WO98/19998 andWO00/34241. Preferred is1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidinedihydrochloride (cf. example 3 of WO98/19998) and(S)1-[(3-hydroxy-1-adamantyl)amino]-acetyl-2-cyano-pyrrolidine (cf.example 1 of W00/34241).

GLP-1 and GLP-1 agonists likewise enhance insulin secretion.

A preferred insulin secretion enhancer is repaglinide and metformin,most preferred is nateglinide.

An insulin sensitivity enhancer restores impaired insulin receptorfunction to reduce insulin resistance and consequently enhance theinsulin sensitivity.

An appropriate insulin sensitivity enhancer is, for example, anappropriate hypoglycemic thiazolidinedione derivative (glitazone).

An appropriate glitazone is, for example,(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione(englitazone),5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione(darglitazone), 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione (ciglitazone),5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(DRF2189),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione(BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637),bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2-4-dione(AD-5075),5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione(DN-108)5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,5{-[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(rosiglitazone),5{-[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione(pioglitazone),5{-[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-thiazolidine-2,4-dione(troglitazone),5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-thiazolidine-2,4-dione(MCC555),5{-[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione(T-174) and5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide(KRP297). Preferred are pioglitazone, rosiglitazone and troglitazone.

The structure of the active agents identified by generic or tradenamesmay be taken from the actual edition of the standard compendium “TheMerck Index” or from databases, e.g. Patents International (e.g. IMSWorld Publications). The corresponding content thereof is herebyincorporated by reference. Any person skilled in the art is fullyenabled to identify the active agents and, based on these references,likewise enabled to manufacture and test the pharmaceutical indicationsand properties in standard test models, both in vitro and in vivo.

Favorable effects can be verified that confirm that hypoglycemic agentssuch as insulin enhancers can restore early phase insulin secretion andreduce post-prandial glucose levels in subjects with IGM. Amulti-center, double-blind, parallel group, randomized study can beconducted in subjects with IGM in order to evaluate the incidence ofconfirmed hypoglycemia and the effects on prandial glucose associatedwith the administration of nateglinide 30 mg, 60 mg or 120 mg or placebobefore each main meal during 8 weeks of treatment. Subjects are selectedon the basis of a 2-hour plasma glucose value after a 75 g oral glucosetolerance test (OGTT) and patients essentially meeting the followingadditional inclusion criteria are included in the study:

-   two-hour glycemia post-OGTT between 7.8 to 11.1 mmol/L (one OGTT to    be performed during the year before entering the study, the second    to be performed within two weeks prior entering the study);-   FPG <7 mmol/L;-   patients are to have a body mass index (BMI) between 20-32 kg/m2;-   patients are to maintain prior diet during the full course of study;-   males, non-fertile females, females of child-bearing potential using    a medically approved birth control method are included;-   the use of other antidiabetics during the trial is not permitted.

Corresponding dosages of e.g. nateglinide are administered with a largeglass of water 2 (BID), 3 (TID) or 4 (QID) times daily depending on thenumber of main meals (breakfast, lunch, snack, dinner). The first doseis to be given with the first main meal (standardized meal i.e. 55%carbohydrates, 25% fat and 20% protein). Visits are scheduled to beperformed at weeks 0, 2, 4 and 8 and the patients are to be fasted forat least 7 hours. All blood samples for laboratory evaluations are drawnbetween 07.00 and 10.00 a.m. HbA1c is to be measured at baseline. andafter 8 weeks of treatment (fasting glucose and fructosamine). Samplesof blood are to be drawn at 10, 20, 20, 60, 120, and 180 minutes afterdrug administration (time 0) and the glucose and insulin levels to bemeasured. At weeks 0 and 8 visits, patients complete a standard mealchallenge containing approximately 500 kcal and measurements of insulinand glucose will be performed.

The findings from analyses of all obtained data in such a study clearlyrevealed that 2 hour prandial glucose levels, HBA1c and fructosaminelevels were surprisingly and significantly reduced, that early phaseinsulin secretion was restored, and that nateglinide could prevent ordelay the progression to type 2 diabetes mellitus. With longer treatmentand follow-up, conditions and diseases associated with IGM could beprevented or reduced.

This type of study in individuals with IGM and particularly IFG and IGTdiffers from those in diabetics since the subjects have normal FPG andare nondiabetics or pre-diabetics.

Surprisingly, hypoglycemic agents as well as a combination ofhypoglycemic agents can be used in subjects with IGM, especially IFGand/or IGT, for the prevention or delay of progression to overt diabetesmellitus type 2; for the prevention, reduction or delay in onset of acondition selected from the group consisting of increased microvascularcomplications; increased cardiovascular morbidity; excesscerebrovascular diseases; increased cardiovascular mortality and suddendeath; higher incidences and mortality rates of malignant neoplasms; andother metabolic disturbances that are associated with IGM.

Furthermore, hypoglycemic agents as well as a combination ofhypoglycemic agents can be used in subjects with IGM, especially IFGand/or IGT, for the prevention, reduction or delay in onset of acondition selected from the group e.g. consisting of retinopathy, otherophthalmic complications of diabetes, nephropathy, neuropathy,peripheral angiopathy, peripheral angiopathy, gangrene, myocardialinfarctions, coronary heart disease, atherosclerosis, other acute andsubacute forms of coronary ischemia, stroke, dyslipidemia,hyperuricemia, hypertension, angina pectoris, microangiopathic changesthat result in amputation, cancer, cancer deaths, obesity, uricemia,insulin resistance, arterial occlusive disease, and atherosclerosis.

According to the present invention, hypoglycemic agents can be used insubjects with IGM, especially with IFG and/or IGT, to prevent or delaythe progression to overt diabetes, to reduce microvascular complicationsof diabetes, to reduce vascular, especially cardiovascular, mortalityand morbidity, especially cardiovascular morbidity and mortality, and toreduce increased mortality related to cancer in individuals with IGT.

Accordingly, the present invention relates to a method in subjects withIGM, especially IFG and/or IGT, for the prevention or delay ofprogression to overt diabetes mellitus type 2; for the prevention,reduction or delay in onset of a condition selected from the groupconsisting of increased microvascular complications; increasedcardiovascular morbidity; excess cerebrovascular diseases; increasedcardiovascular mortality and sudden death; higher incidences andmortality rates of malignant neoplasms; and other metabolic disturbancesthat are associated with IGM.

Especially, the present invention relates to a method used in subjectswith IGM, especially IFG and/or IGT, for the prevention, reduction ordelay in onset of a condition selected from the group e.g. consisting ofretinopathy, other ophthalmic complications of diabetes, nephropathy,neuropathy, peripheral angiopathy, peripheral angiopathy gangrene,myocardial infarctions, coronary heart disease, atherosclerosis, otheracute and subacute forms of coronary ischemia, stroke, dyslipidemia,hyperuricemia, hypertension, angina pectoris, microangiopathic changesthat result in amputation, cancer, cancer deaths, obesity, uricemia,insulin resistance, arterial occlusive disease, and atherosclerosis.

Accordingly, the present invention relates to a method of prevention ordelay of the progression to overt diabetes, especially type 2 (ICD-9Code 250.2), prevention or reduction of microvascular complications likeretinopathy (ICD-9 code 250.5), neurophathy (IDC-9 code 250.6),nephropathy (ICD-9 code 250.4) and peripheral angiopathy or gangrene(ICD-9 code 250.7), later termed “microvascular complications” insubjects with IGM, especially IFG and IGT. Further the present inventionrelates to a method to prevent or reduce conditions of excessivecardiovascular morbidity (ICD-9 codes 410-414), e.g. myocardialinfarction (ICD-9 code 410), arterial occlusive disease, atherosclerosisand other acute and subacute forms of coronary ischemia (ICD-9 code411-414), later termed “cardiovascular morbidity”; to prevent, reduce,or delay the onset of excess cerebrovascular diseases like stroke (ICD-9codes 430-438); to reduce increased cardiovascular mortality (ICD-9codes 390-459) and sudden death (ICD-9 code 798.1); to prevent thedevelopment of cancer (ICD-9 codes 140-208) and to reduce cancer deaths,in each case, in subjects with IGM, especially IFG and IGT. The methodfurther relates to a method of prevention or reduction of othermetabolic disturbances that are associated with IGM includinghyperglycemia (including isolated postprandial hyperglycemia),dyslipidemia (ICD-9 code 272), hyperuricemia (ICD-9 code 790.6) as wellas hypertension (ICD-9 codes 401-404) and angina pectoris (ICD-9 code413.9), in each case, in subjects with IGM, especially IFG and IGT.

The codes identified hereinbefore and herafter according to theInternational Classification of Diseases 9 ^(th) version and thecorresponding definitions allocated thereto are herewith incorporated byreference and likewise form part of the present invention.

The induction by hypoglycemic agents, in particular of early phasesecretion, is rapidly reversible and the reduction of postprandialglucose levels is favorable for prevention or treatment in thisindication.

The method comprises administering to a subject in need thereof aneffective amount of hypoglycemic agents such as an insulin secretionenhancer or a pharmaceutically acceptable salt thereof. A subject inneed of such method is a warm-blooded animal including man.

The present invention also relates to a method to be used in subjectswith IGM, and especially IFG and/or IGT, and associated diseases andconditions such as isolated prandial hyperglycemia, prevention or delayof the progression to overt diabetes, especially type 2, preventionreduction, or delay the onset of microvascular complications, preventionor reduction of gangrene or microangiopathic changes that result inamputation, prevention or reduction of excessive cardiovascularmorbidity and cardiovascular mortality, prevention of cancer andreduction of cancer deaths.

The present invention likewise relates to a method of treatment ofconditions and diseases associated with IGM and especially IFG and/orIGT (including isolated prandial hyperglycemia) including obesity,increased age, diabetes during pregnancy, dyslipidemia, high bloodpressure, uricemia, insulin resistance, arterial occlusive disease,atherosclerosis, retinopathy, nephropathy, angina pectoris, myocardialinfarction, and stroke.

Preferably, said preventions should be effected in individuals withglucose levels in the ranges that have been proven in largeepidemiologic studies to confer increased cardiovascular, microvascularand cancer risk. These levels include levels of plasma glucose ≧7.8mmol/L mmol/L after an OGTT or casual glucose evaluation and/or fastingplasma glucose in the IFG range (fasting plasma glucose between 6.1 and7 mmol/l). As new epidemiologic data become available to lower theglycemic levels that are incontrovertibly linked to the above-mentionedrisks, or as the international standards for defining the IGT and IFGrisk groups are changed, the use of the invention is also warranted fortreatment of the groups at risk.

The present invention also relates to a method to be used in subjectswith IFG comprising administering to a subject in need thereof atherapeutically effective amount of a DPP-IV inhibitor.

The present invention relates to the use of a hypoglycemic agent or apharmaceutically acceptable salt thereof for the manufacture of amedicament in subjects with IGM, especially IFG and/or IGT, for theprevention or delay of progression to overt diabetes mellitus type 2;for the prevention, reduction or delay in onset of a condition selectedfrom the group consisting of increased microvascular complications;increased cardiovascular morbidity; excess cerebrovascular diseases;increased cardiovascular mortality and sudden death; higher incidencesand mortality rates of malignant neoplasms; and other metabolicdisturbances that are associated with IGM.

The present invention relates to the use of an insulin secretionenhancer or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the prevention or delay of theprogression to overt diabetes, especially type 2, prevention orreduction of microvascular complications, prevention or reduction ofexcessive cardiovascular morbidity and cardiovascular mortality,prevention of cancer and reduction of cancer deaths.

The present invention relates to the use of an insulin secretionenhancer or a pharmaceutically acceptable salt for the manufacture of amedicament in subjects with IGM, and especially IFG and/or IGT, andassociated diseases and conditions such as isolated prandialhyperglycemia for the following: prevention or delay of the progressionto overt diabetes, especially type 2, prevention or reduction ofmicrovascular complications, prevention or reduction of excessivecardiovascular morbidity and cardiovascular mortality, prevention ofcancer and reduction of cancer deaths.

The present invention relates to a pharmaceutical composition insubjects with IGM, especially IFG and/or IGT, for the prevention ordelay of progression to overt diabetes mellitus type 2; for theprevention, reduction or delay in onset of a condition selected from thegroup consisting of increased microvascular complications; increasedcardiovascular morbidity; excess cerebrovascular diseases; increasedcardiovascular mortality and sudden death; higher incidences andmortality rates of malignant neoplasms; and other metabolic disturbancesthat are associated with IGM; comprising a hypoglycemic agent or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The present invention relates to a pharmaceutical composition for theprevention or delay of the progression to overt diabetes, especiallytype 2, prevention or reduction of microvascular complications,prevention or reduction of excessive cardiovascular morbidity andcardiovascular mortality, prevention of cancer and reduction of cancerdeaths, comprising an insulin secretion enhancers or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention relates to a pharmaceutical composition insubjects with IGM, and especially IFG and/or IGT and associated diseasesand conditions such as isolated prandial hyperglycemia for thefollowing: prevention or delay of the progression to overt diabetes,especially type 2, prevention or reduction of microvascularcomplications, prevention or reduction of excessive cardiovascularmorbidity and cardiovascular mortality, prevention of cancer andreduction of cancer deaths.

The corresponding active ingredient or a pharmaceutically acceptablesalt thereof may also be used in form of a hydrate or include othersolvents used for crystallization.

Furthermore, the present invention relates to the combination such as acombined preparation or pharmaceutical composition, respectively,comprising at least one insulin secretion enhancer and alt least oneinsulin sensitiser; or at least two insulin secretion enhancers; or atleast two insulin sensitisers; to be used in subjects with IGM,especially IFG and/or IGT, for the prevention or delay of progression toovert diabetes mellitus type 2; for the prevention, reduction or delayin onset of a condition selected from the group consisting of increasedmicrovascular complications; increased cardiovascular morbidity; excesscerebrovascular diseases; increased cardiovascular mortality and suddendeath; higher incidences and mortality rates of malignant neoplasms; andother metabolic disturbances that are associated with IGM.

Further benefits when applying the combination of the present inventionare that lower doses of the individual drugs to be combined according tothe present invention can be used to reduce the dosage, for example,that the dosages need not only often be smaller but are also appliedless frequently, or can be used in order to diminish the incidence ofside effects. This is in accordance with the desires and requirements ofthe patients to be treated.

Preferably, the jointly therapeutically effective amounts of the activeagents according to the combination of the present invention can beadministered simultaneously or sequentially in any order, separately orin a fixed combination.

The term “therapeutically effective amount” shall mean that amount of adrug or combination that will elicit the biological or medical responseneeded to achieve the therapeutic effect as specified according to thepresent invention in the warm-blooded animal, including man. A“therapeutically effective amount” can be administered whenadministering a single hypoglycemic agent and also in both a fixed orfree combination of hypoglycemic agents. A “jointly effective amount” ina combination according to the present invention shall also include anon-effective amount of at least one of the agents to be combined, ifthe overall effect can be achieved by the combined administration of the(fixed or free) combination.

The pharmaceutical composition according to the present invention asdescribed hereinbefore and hereinafter may be used for simultaneous useor sequential use in any order, for separate use or as a fixedcombination.

Preferred components for a combination according to the presentinvention preferably those that are designated as preferred hypoglycemicagents, that are most preferably selected from nateglinide, repaglinide,metformin, pioglitazone, rosiglitazone, troglitazone,1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidine,and (S) 1-[(3-hydroxy-1-adamantyl)amino]-acetyl-2-cyano-pyrrolidine, or,if appropriate, in each case, a pharmaceutically acceptable saltthereof.

In a variation thereof, the present invention likewise relates to a“kit-of-parts”, for example, in the sense that the components to becombined according to the present invention can be dosed independentlyor by use of different fixed combinations with distinguished amounts ofthe components, i.e. simultaneously or at different time points. Theparts of the kit of parts can then e.g. be administered simultaneouslyor chronologically staggered, that is at different time points and withequal or different time intervals for any part of the kit of parts.Preferably, the time intervals are chosen such that the effect on thetreated disease or condition in the combined use of the parts is largerthan the effect that would be obtained by use of only any one of thecomponents.

The invention furthermore relates to a commercial package comprising thecombination according to the present invention together withinstructions for simultaneous, separate or sequential use.

The compounds to be combined can be present as pharmaceuticallyacceptable salts. If these compounds have, for example, at least onebasic center, they can form acid addition salts. Corresponding acidaddition salts can also be formed having, if desired, an additionallypresent basic center. The compounds having an acid group (for exampleCOOH) can also form salts with bases.

Pharmaceutically acceptable salts e.g. of nateglinide are, for example,salts formed with bases, namely cationic salts such as alkali andalkaline earth metal salts, as well as ammonium salts.

The pharmaceutical compositions according to the invention can beprepared in a manner known per se and are those suitable for enteral,such as oral or rectal, and parenteral administration to mammals(warm-blooded animals), including man, comprising a therapeuticallyeffective amount of the pharmacologically active compound, alone or incombination with one or more pharmaceutically acceptable carries,especially suitable for enteral or parenteral application.

The novel pharmaceutical preparations contain, for example, from about10% to about 100%, preferably 80%, preferably from about 20% to about60%, of the active ingredient. Pharmaceutical preparations according tothe invention for enteral or parenteral administration are, for example,those in unit dose forms, such as sugar-coated tablets, tablets,capsules or suppositories, and furthermore ampoules. These arepreparedin a manner known per se, for example by means of conventionalmixing, granulating, sugar-coating, dissolving or lyophilizingprocesses. Thus, pharmaceutical preparations for oral use. can beobtained by combining the active ingredient with solid carriers, ifdesired granulating a mixture obtained, and processing the mixture orgranules, if desired or necessary, after addition of suitable excipientsto give tablets or sugar-coated tablet cores.

The doses for hypoglycemic agents for use according to the presentinvention may, for example, be those that are being used for agents thathave already been launched. For example, tablets of repaglinide in dosesof 0.5 mg, 1 mg or 2 mg of the active ingredient or tablets of metforminin doses of 500 mg or 850 mg of the active ingredient may be takenLikewise these doses may also be used for the agents to be combinedcombination according to the present invention. A person skilled in theart is fully enabled, based on his knowledge, to determine the specificdoses for the specific hypolipidemic agents whether taken alone or incombination.

Nateglinide (I) is preferably administered to the warm-blooded animal ina dosage in the range of about 5 to 1200, more preferably 25 to 800,mg/day, when the warm-blooded animal is a human of about 70 kg bodyweight. Preferred dosages contain 30 mg, 60 mg or 120 mg of nateglindeto be administered preferably before the main meals. Depending on thenumber of main meals the dose regimen are two times a day (BID) or threetimes a day (TID) or four times a day (QID).

The following Examples illustrate the invention described above; theyare not, however, intended to limit the scope of the invention in anyway.

EXAMPLE 1 Tablets of Nateglinide (I)

216,000 tablets, each which contain 120 mg of nateglinide (I) areprepared as follows: Composition: nateglinide (I) 12.960 kg lactose, NF30.564 kg microcrystalline cellulose, NF 15.336 kg povidone, USP 2.592kg croscarmellose sodium, NF 3.974 kg colloidal silicon dioxide, NF1.382 kg magnesium stearate, NF 1.231 kg coating: opadry yellow 1.944 kgpurified water, USP* Q.S.*removed during process

Preparation process: The microcrystalline cellulose, povidone, part ofthe croscarmellose sodium, nateglinide (I) and lactose are mixed in ahigh shear mixer and afterwards granulated using purified water. The wetgranules are dried in a fluid bed dryer and passed through a screen. Thecolloidal silicon dioxide and the rest of the croscarmellose sodium aremixed, passed through a screen and blended with the dried granules in aV-blender. The magnesium stearate is passed through a screen, blendedwith the blend from the V-blender and afterwards the total mixture iscompressed to tablets. The opadry yellow is suspended in purified waterand the tablets are coated with the coating suspension.

EXAMPLE 2 Galenic Formulation of Nateglinide (I) No. 1

intra-granular: nateglinide (I) 120 mg lactose monohydrate 283 mgmicrocrystalline cellulose 142 mg povidone 24 mg croscarmellose sodium24 mg extra-granular: magnesium stearate 7 mg opadry white 20 mg

EXAMPLE 3 Galenic Formulation of Nateglinide (I) No. 2

intra-granular: nateglinide (I) 120 mg lactose monohydrate 283 mgmicrocrystalline cellulose 142 mg povidone 24 mg croscarmellose sodium24 mg extra-granular: croscarmellose sodium 12.8 mg magnesium stearate11.4 mg opadry yellow 18.0 mg colloidal silicon dioxide 12.8 mg

EXAMPLE 4 Tablets of Nateglinide

108,000 tablets, each which contain 120 mg of nateglinide are preparedas follows: Composition: nateglinide 12.960 kg lactose, NF 30.564 kgmicrocrystalline cellulose, NF 15.336 kg povidone, USP 2.592 kgcroscarmellose sodium, NF 3.974 kg colloidal silicon dioxide, NF 1.382kg magnesium stearate, NF 1.231 kg coating: opadry yellow 1.944 kgpurified water, USP* Q.S.*removed during process

Preparation process: The microcrystalline cellulose, povidone, a portionof the croscarmellose sodium, nateglinide and lactose are granulated ina collette gral granulator with the addition of purified water. The wetgranules are dried in a fluid bed dryer and passed through a screen. Thecolloidal silicon dioxide and the rest of the croscarmellose sodium aremixed, passed through a screen and blended with the dried granules in aV-blender. The magnesium stearate is passed through a screen, blendedwith the blend from the V-blender and afterwards the total mixture iscompressed to tablets. The opadry yellow is suspended in purified waterand the tablets are coated with the coating suspension. Variants of thisprocess include adding the colloidal silica and the remainingcroscarmellose sodium to the second granulator load after drying, thenscreening together; and combining as many as 3 granulator/drier loadsper batch.

EXAMPLE 5 Pharmaceutical composition of Nateglinide (120 mg)

nateglinide 120 mg lactose monohydrate 283 mg microcrystalline cellulose142 mg Povidone 24 mg croscarmellose sodium 36.8 mg magnesium stearate11.4 mg opadry yellow 18.0 mg colloidal silicon dioxide 12.8 mg

1. A method for treating or preventing conditions or diseases associatedwith IGT or IFG comprising administering(S)1-[(3-hydroxy-1-adamantyl)amino]-acetyl-2-cyano-pyrrolidine or apharmaceutically acceptable salt thereof to subjects in need thereof. 2.The method of claim 1 for the prevention or delay of progression toovert diabetes mellitus type 2; for the prevention, reduction or delayin onset of a condition selected from the group consisting of increasedmicrovascular complications; increased cardiovascular morbidity; excesscerebrovascular diseases; increased cardiovascular mortality,and suddendeath; higher incidences and mortality rates of malignant neoplasms; andother metabolic disturbances that are associated with IGM.
 3. The methodof claim 1 for the prevention of cancer and reduction of cancer deaths.4. The method of claim 1 for the prevention, reduction or delay in onsetof a condition selected from the group consisting of retinopathy, otherophthalmic complications of diabetes, nephropathy, neuropathy,peripheral angiopathy, peripheral angiopathy or gangrene, myocardialinfarctions, coronary heart disease, atherosclerosis, other acute andsubacute forms of coronary ischemia, stroke, dyslipidemia,hyperuricemia, hypertension, angina pectoris, microangiopathic changesthat result in amputation, cancer, cancer deaths, obesity, uricemia,insulin resistance, arterial occlusive disease, and atherosclerosis. 5.The method of claim 1 for the treatment of diseases or conditionsassociated with isolated prandial hyperglycemia and/or IFG.
 6. Themethod of claim 1 for the prevention of diseases or conditionsassociated with IGT in subjects with prandial glucose excursions having2 hour plasma glucose values between 7.8 to 11.1 mmol/L after an OGTT orcasual glucose test.
 7. The method of claim 5 wherein the disease andcondition associated with isolated prandial hyperglycemia and/or IFG isselected from the group consisting of obesity, increased age, familyhistory of diabetes, diabetes during pregnancy, dyslipidemia, high bloodpressure, uricemia, insulin resistance, arterial occlusive disease,atherosclerosis, retinopathy, nephropathy, angina pectoris, myocardialinfarction, and stroke.